Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2002-03-20
2003-05-27
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S238000
Reexamination Certificate
active
06570012
ABSTRACT:
The present invention relates to new derivatives of octahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid, their preparation process and their use in the preparation of therapeutically active compounds.
A subject of the invention is the compounds of formula (I):
of SR configuration or in the form of an SR+SS mixture, in which R represents a hydrogen atom, an alkyl or aralkyl radical containing up to 18 carbon atoms, the amine function being able to be free or protected.
R represents for example an H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tertbutyl radical, or a benzyl or naphthyl radical. When the amine function is protected, the protection can be carried out according to standard methods for the protection of amines.
A particular subject of the invention is the compounds corresponding to formula (IA):
of SR configuration or in the form of an SR+SS mixture, in which R retains its previous meaning and either R
1
represents
radical
Ra, Rb, Rc and Rd representing an alkyl or aryl radical containing up to 18 carbon atoms, or a mono or polycyclic radical containing one or more heteroatoms, X reoresenting a hydrogen atom, an alkyl radical containing to 8 carbon atoms or an aryl radical containing up to 14 carbon atoms, and R
2
represents a hydrogen atom,
or R
1
and R
2
form together a mono or polycyclic radical containing one or more heteroatoms.
For example, in order to protect the amines, cyclic compounds can be used, for example the
radicals, or also the
radical.
A more particular subject of the invention is the compounds of formula (IA) in which R
1
and R
2
together form a polycyclic radical containing one or more heteroatoms and in particular the compounds corresponding to formula (1A
1
):
of SR configuration or in the form of an SR+SS mixture.
A particular subject of the invention is the compounds of formula (I) in which R represents a methyl radical, of SR configuration or in the form of an SR+SS mixture.
A subject of the invention is also a process characterized in that a compound of formula (II):
in which alk represents an alkyl radical containing up to 8 carbon atoms and Hal represents a halogen atom, is subjected to the action of a compound of formula (III):
in which Aryl represents an aryl radical containing up to 14 carbon atoms, in order to obtain the compound of formula (IV):
which is subjected to the action of a basic agent, in order to obtain the compound of formula (V):
which is optionally subjected to the action of an alkylation agent in order to obtain the compound of formula (VI):
which is subjected to the action of a compound of formula (VII):
in which Hal
1
represents a halogen atom and Ar represents an aryl or aralkyl radical containing up to 18 carbon atoms, R
1
and R
2
retaining the same definition as previously, in order to obtain the compound of formula (VIII):
of SR configuration or in the form of an SR+SS mixture, which is subjected to the action of a hydrogenation agent in order to obtain the compound of formula (IX):
of SR configuration or in the form of an SR+SS mixture, which is subjected to the action of a condensation agent in order to obtain the corresponding compound of formula (IA), then if desired, the amine function is released in order to obtain the compound of formula (I) in which the amine function is free.
In a preferred embodiment:
Hal and Hal
1
represent a chlorine atom,
alk represents an alkyl radical containing up to 4 carbon atoms,
Aryl represents a phenyl or naphthyl radical,
aralkyl represents a benzyl radical,
the reaction between the compounds of formula (II) and formula (III) takes place in the presence of a base for example in the presence of an alkaline carbonate such as potassium carbonate,
the basic agent which is reacted on the compound of formula (IV) is sodium or potassium hydroxide,
the alkylation agent which is reacted on the compound of formula (V) is an alcohol for example methanol,
the condensation between the compounds (VI) and (VII) is carried out in the presence of a base such as pyridine, TEA, diisopropylamine,
the hydrogenation agent is for example hydrogen in the presence of palladium on carbon, palladium dihydroxide in the presence of talc, rhodium in the presence of alumina, ruthenium on carbon, or in the presence of Raney nickel,
the cyclization is carried out in the presence of SOCl
2
or PCl
5
or activated esters or in the presence of dehydration agents such as PTSA,
the release of the amine can be carried out using hydrazine.
The products (IV), (VII), (VIII) and (IX) used during the process are new products and are in themselves a subject of the present invention.
A more particular subject of the invention is the products the preparation of which is given hereafter in the experimental part and in particular the racemic mixture.
A subject of the invention is also the use characterized in that a compound of formula (I) in the form of an SS,SR mixture, or in SR form, is subjected to the action of a deracemization agent of the asymmetric carbon carried by the ring with 6 members, in order to obtain the compound of formula (Iopt):
in SS form, in which the amine function is free or protected and R retains its previous meaning.
A more particular subject of the invention is the use of the compounds of formula (IA) defined above, for the preparation of compounds of formula (IAopt):
in the SS form, in which R, R
1
and R
2
retain their previous meaning,
A more particular subject of the invention is the use characterized in that R represents a methyl radical, and that in which the amine function is protected in the form of phthalimido.
A more particular subject of the invention is the use characterized in that the deracemization agent is a base, more especially a strong base, for example an alkaline or alkaline-earth alcoholate such as sodium or potassium methylate, sodium or potassium terbutylate, or a lithiated amine such as LDA.
A quite particular subject of the invention is the use described hereafter in the experimental part for preparing:
(1s-cis) methyl-9-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -3,4,7,8,9,10-hexahydro-6,10-dioxo-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate.
The product of formula (I) of SS configuration in which R is a terbutyl radical and the amine is protected in the form of phthalimido, is described for example in the Patent EP 94095, this is an intermediate product in the synthesis of products having therapeutic properties.
The products of formula (I) generally can be used for the synthesis of medicaments as indicated in the above patent.
REFERENCES:
patent: 4512924 (1985-04-01), Attwood et al.
patent: 6177565 (2001-01-01), Robidoux
Colladant Colette
Cro-Cq Veronique
Larkin John Patrick
Roussel Patrick
Aventis Pharma S.A.
Habte Kahsay
Muserlian Lucas and Mercanti
Raymond Richard L.
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